HUMORAL AND INTRACARDIAC MECHANISMS OF HEART’ REGULATION.

 

In humans and other mammals, multiple cardiovascular regulatory mechanisms have evolved. These mechanisms increase the blood supply to active tissues and increase or decrease heat loss from the body by redistributing the blood. In the face of challenges such as hemorrhage, they maintain the blood flow to the heart and brain. When the challenge faced is severe, flow to these vital organs is maintained at the expense of the circulation to the rest of the body.

Circulatory adjustments are effected by altering the output of the pump (the heart), changing the diameter of the resistance vessels (primarily the arterioles), or altering the amount of blood pooled in the capacitance vessels (the veins). Regulation of cardiac output is discussed in Chapter 29. The caliber of the arterioles is adjusted in part by autoregulation. It is also increased in active tissues by locally produced vasodilator metabolites, is affected by substances secreted by the endothelium, and is regulated systemically by circulating vasoactive substances and the nerves that innervate the arterioles. The caliber of the capacitance vessels is also affected by circulating vasoactive substances and by vasomotor nerves. The systemic regulatory mechanisms synergize with the local mechanisms and adjust vascular responses throughout the body.

The terms vasoconstriction and vasodilation are generally used to refer to constriction and dilation of the resistance vessels. Changes in the caliber of the veins are referred to specifically as venoconstriction or venodilation.

LOCAL REGULATION

Autoregulation

The capacity of tissues to regulate their own blood flow is referred to as autoregulation. Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance, so that blood flow remains relatively constant. This capacity is well developed in the kidneys (see Chapter 38), but it has also been observed in the mesentery, skeletal muscle, brain, liver, and myocardium. It is probably due in part to the intrinsic contractile response of smooth muscle to stretch (myogenic theory of autoregulation). As the pressure rises, the blood vessels are distended and the vascular smooth muscle fibers that surround the vessels contract. If it is postulated that the muscle responds to the tension in the vessel wall, this theory could explain the greater degree of contraction at higher pressures; the wall tension is proportionate to the distending pressure times the radius of the vessel (law of Laplace; see Chapter 30), and the maintenance of a given wall tension as the pressure rises would require a decrease in radius. Vasodilator substances tend to accumulate in active tissues, and these "metabolites" also contribute to autoregulation (metabolic theory of autoregulation). When blood flow decreases, they accumulate and the vessels dilate; when blood flow increases, they tend to be washed away.

Vasodilator Metabolites

The metabolic changes that produce vasodilation include, in most tissues, decreases in O2 tension and pH. These changes cause relaxation of the arterioles and precapillary sphincters. Increases in CO2 tension and osmolality also dilate the vessels. The direct dilator action of CO2 is most pronounced in the skin and brain. The neurally mediated vasoconstrictor effects of systemic as opposed to local hypoxia and hypercapnia are discussed below. A rise in temperature exerts a direct vasodilator effect, and the temperature rise in active tissues (due to the heat of metabolism) may contribute to the vasodilation. K+ is another substance that accumulates locally, has demonstrated dilator activity, and probably plays a role in the dilation that occurs in skeletal muscle. Lactate may also contribute to the dilation. In injured tissues, histamine released from damaged cells increases capillary permeability. Thus, it is probably responsible for some of the swelling in areas of inflammation. Adenosine may play a vasodilator role in cardiac muscle but not in skeletal muscle. It also inhibits the release of norepinephrine.

Localized Vasoconstriction

Injured arteries and arterioles constrict strongly. The constriction appears to be due in part to the local liberation of serotonin from platelets that stick to the vessel wall in the injured area (see Chapter 27). Injured veins also constrict.

A drop in tissue temperature causes vasoconstriction, and this local response to cold plays a part in temperature regulation (see Chapter 14).

SUBSTANCES SECRETED BY THE ENDOTHELIUM

Endothelial Cells

As noted in Chapter 30, the endothelial cells make up a large and important organ. This organ secretes many growth factors and vasoactive substances. The vasoactive substances include prostaglandins and thromboxanes, nitric oxide, and endothelins.

Prostacyclin & Thromboxane A2

Prostacyclin is produced by endothelial cells and thromboxane A2 by platelets from their common precursor arachidonic acid via the cyclooxygenase pathway (see Figure 17-33). Thromboxane A2 promotes platelet aggregation and vasoconstriction, whereas prostacyclin inhibits platelet aggregation and promotes vasodilation. The balance between platelet thromboxane A2 and prostacyclin fosters localized platelet aggregation and consequent clot formation (see Chapter 27) while preventing excessive extension of the clot and maintaining blood flow around it.

The thromboxane A2-prostacyclin balance can be shifted toward prostacyclin by administration of low doses of aspirin. Aspirin produces irreversible inhibition of cyclooxygenase by acetylating a serine residue in its active site. Obviously, this reduces production of both thromboxane A2 and prostacyclin. However, endothelial cells produce new cyclooxygenase in a matter of hours whereas platelets cannot manufacture the enzyme, and the level rises only as new platelets enter the circulation. This is a slow process because platelets have a half-life of about 4 days. Therefore, administration of small amounts of aspirin for prolonged periods reduces clot formation and has been shown to be of value in preventing myocardial infarctions, unstable angina, transient ischemic attacks, and stroke.

Endothelium-Derived Relaxing Factor

A chance observation 2 decades ago led to the discovery that the endothelium plays a key role in vasodilation. Many different stimuli act on the endothelial cells to produce endothelium-derived relaxing factor (EDRF), a substance that is now known to be nitric oxide (NO). NO is synthesized from arginine (Figure 31-1) in a reaction catalyzed by nitric oxide synthase (NO synthase, NOS). Three isoforms of NOS have been identified: NOS 1, found in the nervous system; NOS 2, found in macrophages and other immune cells; and NOS 3, found in endothelial cells. NOS 1 and NOS 3 are activated by agents that increase intracellular Ca2+ concentration, including the vasodilators acetylcholine and bradykinin. The NOS in immune cells is not induced by Ca2+ but is activated by cytokines. The NO that is formed in the endothelium diffuses to smooth muscle cells, where it activates soluble guanylyl cyclase, producing cGMP (Figure 31-1), which in turn mediates the relaxation of vascular smooth muscle. NO is inactivated by hemoglobin.

Adenosine, ANP, and histamine via H2 receptors produce relaxation of vascular smooth muscle that is independent of the endothelium. However, acetylcholine, histamine via H1 receptors, bradykinin, VIP, substance P, and some other polypeptides act via the endothelium, and various vasoconstrictors that act directly on vascular smooth muscle would produce much greater constriction if they did not simultaneously cause the release of NO. When flow to a tissue is suddenly increased by arteriolar dilation, the large arteries to the tissue also dilate. This flow-induced dilation is due to local release of NO. Products of platelet aggregation also cause release of NO, and the resulting vasodilation helps keep blood vessels with an intact endothelium patent. This is in contrast to injured blood vessels, where the endothelium is damaged at the site of injury and platelets therefore aggregate and produce vasoconstriction.

Further evidence for a physiologic role of NO is the observation that when various derivatives of arginine that inhibit NO synthase are administered to experimental animals, there is a prompt rise in blood pressure. This suggests that tonic release of NO is necessary to maintain normal blood pressure.


NO is also involved in vascular remodeling and angiogenesis, and NO may be involved in the pathogenesis of atherosclerosis. It is interesting in this regard that some patients with heart transplants develop an accelerated form of atherosclerosis in the vessels of the transplant, and there is reason to believe that this is triggered by endothelial damage. Nitroglycerin and other nitrovasodilators that are of great value in the treatment of angina act by stimulating guanylyl cyclase in the same manner as NO does.

There is good evidence that penile erection is produced by release of NO, with consequent vasodilation and engorgement of the corpora cavernosa.

Other Functions of NO

It has become almost commonplace to discover a compound that plays an important role in cardiovascular regulation and then learn that it is produced in other systems and has additional diverse functions. This is true, for example, of angiotensin II (see Chapter 24) and the endothelins (see below). It is also true of NO. NO is present in the brain, and, acting via cGMP, it is important in brain function (see Chapter 4). It is necessary for the cytotoxic activity of macrophages, including their ability to kill cancer cells. In the gastrointestinal tract, it is a major dilator of smooth muscle. Other functions of NO are mentioned in other parts of this book.

The production of CO from heme is shown in Figure 4-33. HO2, the enzyme that catalyzes the reaction, is present in cardiovascular tissues, and there is evidence that CO as well as NO produces local dilation in blood vessels.

Endothelins

Endothelial cells also produce endothelin-1, one of the most potent vasoconstrictor agents yet isolated. Endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3) are the members of a family of three similar 21-amino-acid polypeptides (Figure 31-2). Each is encoded by a different gene. The unique structure of the endothelins resembles that of the sarafotoxins, polypeptides found in the venom of a snake, the Israeli burrowing asp.

Endothelin-1

In endothelial cells, the product of the endothelin-1 gene is processed to a 39-amino-acid prohormone, big endothelin-1, which has about 1% of the activity of endothelin-1. The prohormone is cleaved at a Trp-Val bond to form endothelin-1 by endothelin-converting enzyme. There is a family of these enzymes, apparently related to the cleavage of big endothelin-2 and big endothelin-3 as well as big endothelin-1. Small amounts of big endothelin-1 and endothelin-1 are secreted into the blood, but for the most part, they are secreted into the media of blood vessels and act in a paracrine fashion.

Two different endothelin receptors have been cloned, both of which are coupled via G proteins to phospholipase C. The ETA receptor, which is specific for endothelin-1, is found in many tissues and mediates the vasoconstriction produced by endothelin-1. The ETB receptor responds to all three endothelins, and is coupled to Gi. It may mediate vasodilation, and it appears to mediate the developmental effects of the endothelins (see below).

Regulation of Secretion

Endothelin-1 is not stored in secretory granules, and most regulatory factors alter the transcription of its gene, with changes in secretion occurring promptly thereafter.

Cardiovascular Functions

As noted above, endothelin-1 appears to be primarily a local, paracrine regulator of vascular tone. Big endothelin-1 and endothelin-1 are both present in the circulation. However, they are not increased in hypertension, and in mice in which one allele of the endothelin-1 gene is knocked out, blood pressure is actually elevated rather than reduced. The concentration of circulating endothelin-1 is elevated in congestive heart failure and after myocardial infarction, so it may play a role in the pathophysiology of these diseases.

Other Functions of Endothelins

Endothelin-1 is found in the brain and kidneys as well as the endothelial cells. Endothelin-2 is produced primarily in the kidneys and intestine. Endothelin-3 is present in the blood and is found in high concentrations in the brain. It is also found in the kidneys and gastrointestinal tract. In the brain, endothelins are abundant and, in early life, are produced by both astrocytes and neurons. They are found in the dorsal root ganglia, ventral horn cells, the cortex, the hypothalamus, and cerebellar Purkinje cells. They also play a role in regulating transport across the blood-brain barrier. There are endothelin receptors on mesangial cells, and the polypeptide presumably produces mesangial cell-mediated decreases in the glomerular filtration rate.

Mice that have both alleles of the endothelin-1 gene deleted have severe craniofacial abnormalities and die of respiratory failure at birth. They also have megacolon (Hirschsprung's disease), apparently because the cells that normally form the myenteric plexus fail to migrate to the distal colon. In addition, endothelins play a role in closing the ductus arteriosus at birth.

SYSTEMIC REGULATION BY HORMONES

Many circulating hormones affect the vascular system. The vasodilator hormones include kinins, VIP, and ANP. Circulating vasoconstrictor hormones include vasopressin, norepinephrine, epinephrine, and angiotensin II.

Kinins

Two related vasodilator peptides called kinins are found in the body. One is the nonapeptide bradykinin, and the other is the decapeptide lysylbradykinin, also known as kallidin. Lysylbradykinin can be converted to bradykinin by aminopeptidase. Both peptides are metabolized to inactive fragments by kininase I, a carboxypeptidase that removes the carboxyl terminal Arg. In addition, the dipeptidylcarboxypeptidase kininase II inactivates bradykinin and lysylbradykinin by removing Phe-Arg from the carboxyl terminal. Kininase II is the same enzyme as angiotensin-converting enzyme, which removes His-Leu from the carboxyl terminal end of angiotensin I.

Bradykinin and lysylbradykinin are formed from two precursor proteins, high-molecular-weight kininogen and low-molecular-weight kininogen. They are formed by alternative splicing of a single gene located on chromosome 3. The biologic activities of bradykinin and lysylbradykinin are generally similar, and it is not known why two types are produced.

Proteases called kallikreins release the peptides from their precursors. They are produced in humans by a family of three genes located on chromosome 19. There are two types of kallikreins: plasma kallikrein, which circulates in an inactive form, and tissue kallikrein, which appears to be located primarily on the apical membranes of cells concerned with transcellular electrolyte transport. Tissue kallikrein is found in many tissues, including sweat and salivary glands, the pancreas, the prostate, the intestine, and the kidneys. Tissue kallikrein acts on high-molecular-weight kininogen and low-molecular-weight kininogen to form lysylbradykinin. When activated, plasma kallikrein acts on high-molecular-weight kininogen to form bradykinin.

Inactive plasma kallikrein (prekallikrein) is converted to the active form, kallikrein, by active factor XII, the factor which initiates the intrinsic blood clotting cascade. Kallikrein also activates factor XII in a positive feedback loop, and high-molecular-weight kininogen has a factor XII-activating action.

The actions of the kinins resemble those of histamine. They are primarily tissue hormones, although small amounts are also found in the circulating blood. They cause contraction of visceral smooth muscle, but they relax vascular smooth muscle via NO, lowering blood pressure. They also increase capillary permeability, attract leukocytes, and cause pain upon injection under the skin. They are formed during active secretion in sweat glands, salivary glands, and the exocrine portion of the pancreas, and they are probably responsible for the increase in blood flow when these tissues are actively secreting their products. They are present in the kidneys, where their function is uncertain.

Two bradykinin receptors, B1 and B2, have been identified. Their amino acid residues are 36% identical, and both are serpentine receptors coupled to G proteins. The B1 receptor may mediate the pain-producing effects of the kinins, but little is known about its distribution and function. The B2 receptor has strong homology to the H2 receptor and is found in many different tissues.

Adrenomedullin

Adrenomedullin (AM) is a depressor polypeptide first isolated from pheochromocytoma cells. Its prohormone is also the source of another depressor polypeptide, proadrenomedullin amino terminal 20 peptide (PAMP). AM also inhibits aldosterone secretion in salt-depleted animals and appears to produce its depressor effect by increasing production of NO. PAMP appears to act by inhibiting peripheral sympathetic nerve activity. Both AM and PAMP are found in plasma and in many tissues in addition to the adrenal medulla, including the kidney and the brain. However, the role, if any, of AM and PAMP in cardiovascular control is still unknown.

Natriuretic Hormones

The atrial natriuretic peptide (ANP) secreted by the heart antagonizes the action of various vasoconstrictor agents and lowers blood pressure, but its exact role in the regulation of the circulation is still unsettled. The natriuretic Na+-K+ ATPase inhibitor, which is now thought to be endogenously produced ouabain, apparently raises rather than lowers blood pressure.

Circulating Vasoconstrictors

Vasopressin is a potent vasoconstrictor, but when it is injected in normal individuals, there is a compensating decrease in cardiac output, so that there is little change in blood pressure.

Norepinephrine has a generalized vasoconstrictor action, whereas epinephrine dilates the vessels in skeletal muscle and the liver. The relative unimportance of circulating norepinephrine, as opposed to norepinephrine released from vasomotor nerves,  where the cardiovascular actions of catecholamines are discussed in detail.

The octapeptide angiotensin II has a generalized vasoconstrictor action. It is formed from angiotensin I liberated by the action of renin from the kidney on circulating angiotensinogen. Its formation is increased because renin secretion is increased when the blood pressure falls or ECF volume is reduced, and it helps maintain blood pressure. Angiotensin II also increases water intake and stimulates aldosterone secretion, and increased formation of angiotensin II is part of a homeostatic mechanism that operates to maintain ECF volume. In addition, there are renin-angiotensin systems in many different organs, and there may be one in the walls of blood vessels. Angiotensin II produced in blood vessel walls could be important in some forms of clinical hypertension.

Urotensin-II, a polypeptide first isolated from the spinal cord of fish, is present in human cardiac and vascular tissue. It is one of the most potent mammalian vasoconstrictors known, but its physiologic role is still uncertain.

SYSTEMIC REGULATION BY THE NERVOUS SYSTEM

Neural Regulatory Mechanisms

Although the arterioles and the other resistance vessels are most densely innervated, all blood vessels except capillaries and venules contain smooth muscle and receive motor nerve fibers from the sympathetic division of the autonomic nervous system. The fibers to the resistance vessels regulate tissue blood flow and arterial pressure. The fibers to the venous capacitance vessels vary the volume of blood "stored" in the veins. The innervation of most veins is sparse, but the splanchnic veins are well innervated. Venoconstriction is produced by stimuli that also activate the vasoconstrictor nerves to the arterioles. The resultant decrease in venous capacity increases venous return, shifting blood to the arterial side of the circulation.

Innervation of the Blood Vessels

Noradrenergic fibers end on vessels in all parts of the body. The noradrenergic fibers are vasoconstrictor in function. In addition to their vasoconstrictor innervation, the resistance vessels of the skeletal muscles are innervated by vasodilator fibers, which, although they travel with the sympathetic nerves, are cholinergic (the sympathetic vasodilator system.) There is some evidence that blood vessels in the heart, lungs, kidneys, and uterus also receive a cholinergic innervation. Bundles of noradrenergic and cholinergic fibers form a plexus on the adventitia of the arterioles. Fibers with multiple varicosities extend from this plexus to the media and end primarily on the outer surface of the smooth muscle of the media without penetrating it. Transmitters reach the inner portions of the media by diffusion, and current spreads from one smooth muscle cell to another via gap junctions.

There is no tonic discharge in the vasodilator fibers, but the vasoconstrictor fibers to most vascular beds have some tonic activity. When the sympathetic nerves are cut (sympathectomy), the blood vessels dilate. In most tissues, vasodilation is produced by decreasing the rate of tonic discharge in the vasoconstrictor nerves, although in skeletal muscles it can also be produced by activating the sympathetic vasodilator system.

Nerves containing polypeptides are found on many blood vessels. The cholinergic nerves also contain VIP, which produces vasodilation. The noradrenergic postganglionic sympathetic nerves also contain neuropeptide Y, which is a vasoconstrictor. Substance P and CGRPα, which produce vasodilation, are found in sensory nerves near blood vessels.

Afferent impulses in sensory nerves from the skin are relayed antidromically down branches of the sensory nerves that innervate blood vessels, and these impulses cause release of substance P from the nerve endings. Substance P causes vasodilation and increased capillary permeability. This local neural mechanism is called the axon reflex (see Figure 32-17). Other cardiovascular reflexes are integrated in the central nervous system.

Cardiac Innervation

Impulses in the noradrenergic sympathetic nerves to the heart increase the cardiac rate (chronotropic effect) and the force of cardiac contraction (inotropic effect). They also inhibit the effects of vagal stimulation, probably by release of neuropeptide Y, which is a cotransmitter in the sympathetic endings. Impulses in the cholinergic vagal cardiac fibers decrease the heart rate. There is a moderate amount of tonic discharge in the cardiac sympathetic nerves at rest, but there is a good deal of tonic vagal discharge (vagal tone) in humans and other large animals. When the vagi are cut in experimental animals, the heart rate rises, and after the administration of parasympatholytic drugs such as atropine, the heart rate in humans increases from 70, its normal resting value, to 150-180 beats/min because the sympathetic tone is unopposed. In humans in whom both noradrenergic and cholinergic systems are blocked, the heart rate is approximately 100.

Vasomotor Control

The sympathetic nerves that constrict arterioles and veins and increase heart rate and stroke volume discharge in a tonic fashion, and blood pressure is adjusted by variations in the rate of this tonic discharge. Spinal reflex activity affects blood pressure, but the main control of blood pressure is exerted by groups of neurons in the medulla oblongata that are sometimes called collectively the vasomotor area or vasomotor center. Neurons that mediate increased sympathetic discharge to blood vessels and the heart project directly to sympathetic preganglionic neurons in the intermediolateral gray column (IML) of the spinal cord. On each side, the cell bodies of these neurons are located near the pial surface of the medulla in the rostral ventrolateral medulla (RVLM). Their axons course dorsally and medially and then descend in the lateral column of the spinal cord to the IML. They contain PNMT, but it appears that the excitatory transmitter they secrete is glutamate rather than epinephrine.

Impulses reaching the medulla also affect the heart rate via vagal discharge to the heart. The neurons from which the vagal fibers arise are in the dorsal motor nucleus of the vagus and the nucleus ambiguus.

When vasoconstrictor discharge is increased, there is increased arteriolar constriction and a rise in blood pressure. Venoconstriction and a decrease in the stores of blood in the venous reservoirs usually accompany these changes, although changes in the capacitance vessels do not always parallel changes in the resistance vessels. Heart rate and stroke volume are increased because of activity in the sympathetic nerves to the heart, and cardiac output is increased. There is usually an associated decrease in the tonic activity of vagal fibers to the heart. Conversely, a decrease in vasomotor discharge causes vasodilation, a fall in blood pressure, and an increase in the storage of blood in the venous reservoirs. There is usually a concomitant decrease in heart rate, but this is mostly due to stimulation of the vagal innervation of the heart.

Afferents to the Vasomotor Area

The afferents that converge on the vasomotor area include not only the very important fibers from arterial and venous baroreceptors but also fibers from other parts of the nervous system and from the carotid and aortic chemoreceptors. In addition, some stimuli act directly on the vasomotor area.

There are descending tracts to the vasomotor area from the cerebral cortex (particularly the limbic cortex) that relay in the hypothalamus. These fibers are responsible for the blood pressure rise and tachycardia produced by emotions such as sexual excitement and anger. The connections between the hypothalamus and the vasomotor area are reciprocal, with afferents from the brain stem closing the loop.

Inflation of the lungs causes vasodilation and a decrease in blood pressure. This response is mediated via vagal afferents from the lungs that inhibit vasomotor discharge. Pain usually causes a rise in blood pressure via afferent impulses in the reticular formation converging on the vasomotor area. However, prolonged severe pain may cause vasodilation and fainting.

Somatosympathetic Reflex

Pain causes increased arterial pressure, and activity in afferents from exercising muscles probably exerts a similar pressor effect via the C1 neurons in the rostral ventrolateral medulla. The pressor response to stimulation of somatic afferent nerves is called the somatosympathetic reflex.

Baroreceptors

The baroreceptors are stretch receptors in the walls of the heart and blood vessels. The carotid sinus and aortic arch receptors monitor the arterial circulation. Receptors are also located in the walls of the right and left atria at the entrance of the superior and inferior venae cavae and the pulmonary veins, as well as in the pulmonary circulation. These receptors in the low-pressure part of the circulation are referred to collectively as the cardiopulmonary receptors. The baroreceptors are stimulated by distention of the structures in which they are located, and so they discharge at an increased rate when the pressure in these structures rises. Their afferent fibers pass via the glossopharyngeal and vagus nerves to the medulla. Most of them end in the nucleus of the tractus solitarius (NTS), and the excitatory transmitter they secrete is probably glutamate. There are excitatory, presumably glutaminergic, projections from the NTS to the caudal and intermediate ventrolateral medulla, where they apparently stimulate GABA-secreting inhibitory neurons that project to the rostral ventrolateral medulla. There are also excitatory projections, probably polyneuronal, from the NTS to the vagal motor neurons in the dorsal motor nucleus and the nucleus ambiguus. Thus, increased baroreceptor discharge inhibits the tonic discharge of the vasoconstrictor nerves and excites the vagal innervation of the heart, producing vasodilation, venodilation, a drop in blood pressure, bradycardia, and a decrease in cardiac output.

Carotid Sinus & Aortic Arch

The carotid sinus is a small dilation of the internal carotid artery just above the bifurcation of the common carotid into external and internal carotid branches. Baroreceptors are located in this dilation. They are also found in the wall of the arch of the aorta. The receptors are located in the adventitia of the vessels. They are extensively branched, knobby, coiled, and intertwined ends of myelinated nerve fibers that resemble Golgi tendon organs. Similar receptors have been found in various other parts of the large arteries of the thorax and neck in some species. The afferent nerve fibers from the carotid sinus and carotid body form a distinct branch of the glossopharyngeal nerve, the carotid sinus nerve, but the fibers from the aortic arch form a separate distinct branch of the vagus only in the rabbit. The carotid sinus nerves and vagal fibers from the aortic arch are commonly called the buffer nerves.

Buffer Nerve Activity

At normal blood pressure levels, the fibers of the buffer nerves discharge at a low rate (Figure 31-10). When the pressure in the sinus and aortic arch rises, the discharge rate increases; and when the pressure falls, the rate declines.

When one carotid sinus of a monkey is isolated and perfused and the other baroreceptors are denervated, there is no discharge in the afferent fibers from the perfused sinus and no drop in the animal's arterial pressure or heart rate when the perfusion pressure is below 30 mm Hg. At perfusion pressures of 70-110 mm Hg, there is an essentially linear relation between the perfusion pressure and the fall in blood pressure and heart rate produced in the monkey. At perfusion pressures above 150 mm Hg there is no further increase in response, presumably because the rate of baroreceptor discharge and the degree of inhibition of the vasomotor center are maximal.

The carotid receptors respond both to sustained pressure and to pulse pressure. A decline in carotid pulse pressure without any change in mean pressure decreases the rate of baroreceptor discharge and provokes a rise in blood pressure and tachycardia. The receptors also respond to changes in pressure as well as steady pressure; when the pressure is fluctuating, they sometimes discharge during the rises and are silent during the falls at mean pressures at which if there were no fluctuations, there would be a steady discharge.

The aortic receptors have not been studied in such great detail, but there is no reason to believe that their responses differ significantly from those of the receptors in the carotid sinus.

From the foregoing discussion, it is apparent that the baroreceptors on the arterial side of the circulation, their afferent connections to the vasomotor and cardioinhibitory areas, and the efferent pathways from these areas constitute a reflex feedback mechanism that operates to stabilize the blood pressure and heart rate. Any drop in systemic arterial pressure decreases the inhibitory discharge in the buffer nerves, and there is a compensatory rise in blood pressure and cardiac output. Any rise in pressure produces dilation of the arterioles and decreases cardiac output until the blood pressure returns to its previous normal level.